Toward the objective of Growth Control in MM, Project 1 continues its path of translational research based on the concept that control of a malignancy with enornnous genomic instability requires effective interference with redundant escape mechanisms via multi-targeted combination therapy as delivered in Total Therapy (TT). Unprecedented success in gene expression profiling (GEP)-defined low-risk and lack of substantive progress in high-risk MM provided the rationale for adopting a risk-based treatment approach in Aim 1, hypothesizing that overall progress in MM growth control can be accelerated by GEP-defined riskbased therapies. TT4 for low-risk MM emphasizes reduction of morbidity while retaining TT3 efficacy with 4- yr continuous CR estimates of 90%. Appreciating MM re-growth during prolonged treatment recovery phases of TT3 as a mechanism of treatment failure, TT5 for high-risk MM will apply dose-dense but less doseintense therapy to provide quasi-continuous exposure to 8-drug synergistic combinations as a means of avoiding host exhaustion. Translational research emphasizes pharmacogenomic studies into the mechanisms of action of bortezomib and, for the first time, of melphalan, whose synergistic interaction with novel agents will be maximally exploited. Taking full advantage of the enormous repository of protocolspecified serial GEP samples and imaging studies in TT2 and TT3, follow-up over the next 5 years will enable us to test the hypothesis that therapeutic success in TT3 compared with TT2 can be explained in the context of MM-microenvironment (ME) interaction revealed by GEP studies of both MM and the ME. Aim 2 will interrogate the MM-ME interaction viewed as critical toward disease manifestation, progression, and therapeutic response. We expect to unravel resistance mechanisms due to expansion of primary resistant tumor subpopulations or secondary transformation events with high LDH and human myeloma cell line (HMCL) signatures; derive cure signatures for patients in continuous CR for more than 7 yr; identify thalidomide and bortezomib beneficiaries toward future individualized therapy; determine whether drug (bortezomib, melphalan) test-doseinduced GEP alterations provide insight into molecular disease evolution; determine whether reactivation of tumor dormancy at focal lesion sites is responsible for late and unexpected relapses; and elucidate whether and how myeloma cells may uniquely interact, in a molecular subtype-specific fashion, with the ME and thus contribute to disease manifestation and progression events.